1. Technical Field
This invention relates to the field of vaccines used as cancer therapy.
2. Background
A vaccine is one of the most efficacious, safe, nontoxic and economical weapons to prevent disease and to control the spread of disease. Conventional vaccines are a form of immunoprophylaxis given before disease occurrence to afford immunoprotection by generating a strong host immunological memory against a specific antigen. The primary aim of vaccination is to activate the adaptive specific immune response, primarily to generate B and T lymphocytes against specific antigen(s) associated with the disease or the disease agent.
Similarly, cancer vaccines aim to generate immune responses against cancer tumor-associated antigens. Cancers can be immunogenic and can activate host immune responses capable of controlling the disease and causing tumor regression. However, cancer at the same time can be specifically and nonspecifically immunosuppressive and can evade the host""s immune system. Many protein/glycoprotein tumor-associated antigens have been identified and linked to certain types of cancer. MAGE-3, MAGE-1, gp100, TRP-2, tyrosinase, MART-1, xcex2-HCG, CEA, Ras; B-catenin, gp43, GAGE-1, BAGE-1, PSA, MUC-1,2,3, and HSP-70 are just a few examples.
Multiple approaches are being assessed in immunizing cancer patients with tumor-associated antigens (TAAs). Vaccines in clinical use fall into several categories determined by their cellular components, which range from whole cells to immunogenic peptides. Whole cell and cell lysate vaccines can be autologous or allogeneic vaccines, depending on the host origin of the cancer cells. An autologous whole cell cancer vaccine is a patient-specific formulation made from the host""s tumor. Autologous cancer vaccines generally are not clinically successful unless they are modified. Because they are patient-specific, they also are costly and limited to those patients from whom cancer cells can be obtained in sufficient quantity to produce a single-cell suspension. In addition, the inherently limited number of cells is problematic with respect to multiple vaccinations, making an autologous formulation impractical for prophylaxis or treatment of early disease. Some of these problems are solved with allogeneic whole cell vaccines or genetically engineered whole cell vaccines. However, these methods may be tedious and time consuming. In addition, genetically engineered whole cell vaccines must be tested for antigenicity and immunogenicity. Current animal tumor models are not truly representative of human cancer tumors.
Natural and recombinant cancer protein antigen vaccines are subunit vaccines. Unlike whole cell vaccines, these subunit vaccines contain defined immunogenic antigens at standardized levels. The key problem with such vaccines is finding the right adjuvant and delivery system. In addition, purification of natural or recombinant tumor antigens is tedious and not always logistically practical. Human cancer vaccines require culturing tumor cells, purifying tumor antigens, or producing specific peptides or recombinant proteins. In addition, there are problems related to antigen presentation and host major histocompatibility complex (MHC) polymorphism.
Vaccines which include nucleic acid encoding the tumor antigens rather than vaccines comprising the antigen itself address some of these problems. The host normal cells (nonhemopoietic) can express and present the tumor antigens to the immune system. In general, when a cytopathic virus infects a host normal cell, the viral proteins are endogenously processed and presented on the cell surface, or in fragments by MHC molecules. Foreign defined nucleic acid transfected and expressed by normal cells can mimic viral infections.
DNA vaccines recently have been shown to be a promising approach for immunization against a variety of infectious diseases. Michel, M L et al., Huygen, K, et al., and Wang, B, et al. Delivery of naked DNAs containing microbial antigen genes can induce antigen-specific immune responses in the host. The induction of antigen-specific immune responses using DNA-based vaccines has shown some promising effects. Wolff, J. A., et al. Recent studies have demonstrated the potential feasibility of immunization using a DNA-mediated vaccine for CEA and MUC-1. Conry, R. M., et al. and Graham, R. A., et al.
DNA-based vaccination has shown to have a greater degree of control of antigen expression, toxicity and pathogenicity over live attenuated virus immunization. However, although in vivo DNA vaccination protocols are available, improvements in in vivo delivery and transgene expression are needed. For example, introduction of DNA into specific cells often results in degradation of the DNA by endosomes or lysosomes. Vaccines that require the tumor antigen to be expressed by tumor cells may result in problems such as suppression of immune responses or altered physiologic functions that modify antigen expression because tumor cells have many negative type regulating elements. Current approaches of in vivo delivery of DNA by retroviral or adenoviral vectors have problems related to efficacy, viral gene integration, potential pathogenic activity and immune response to viral vector encoding proteins. In addition, the DNA in DNA vaccines may be incorporated into the host cell""s DNA, making it difficult to halt production of the tumor antigen when treatment is complete. Some liposome delivery systems are undesirable because they may incorporate into hemopoietic-derived cells such as lymphocytes.
The invention provides methods and compositions for immunizing against a tumor-associated antigen, suppressing or attenuating tumor growth, and treating cancer. The methods and compositions provided may induce an antibody response through IgG, IgM, or IgA molecules, or a cell-mediated response through CD4, CD8 or other T cell subsets.
The compositions provided by the invention are comprised of viral liposomes comprising nucleic acid, preferably RNA, encoding a tumor-associated antigen. The viral liposomes may be formed by the fusion of HVJ reagents with nonviral reagents. The nucleic acid may be DNA or RNA. The tumor-associated antigen may be any antigen known to be associated with tumors, for example MAGE-1, MAGE-3, gp100, TRP-2, tyrosinase, MART-1, xcex2-HCG, or HSP-70. The compositions of the antigens may be chimeric with other molecules that may include diphtheria toxin, other immunogenic toxin peptides or helper antigen peptides. The compositions may include other components, such as HMG-1, that direct the nucleic acid to a certain location in the cell or direct translation of the tumor-associated antigen.
The methods provided by the invention comprise administering a vaccine comprised of viral liposomes comprising nucleic acid encoding a tumor-associated antigen. The vaccine may be administered subcutaneously, intradermally, intramuscularly, or into an organ. The vaccine may be administered in a way that induces a host normal cell to express the tumor-associated antigen.